The invention relates generally to novel substituted 2-amino-4-phenyl-dihydroquinolines compounds and compositions comprising them. Pharmaceutical compositions comprising compounds of this type are useful in the prevention or treatment of various disorders. Thus, the compounds can be employed inter alia for renal disorders such as acute or chronic renal failure, for impairments of biliary function, for respiratory impairments such as snoring or sleep apneas or for stroke.
The compounds according to the invention are effective inhibitors of the cellular sodium-proton transporter (Na/H exchanger) which is elevated in numerous disorders (essential hypertension, atherosclerosis, diabetes, etc.), also in those cells which are readily amenable to measurements, such as, for example, in erythrocytes, platelets or leukocytes. The compounds used according to the invention are therefore suitable as excellent and simple scientific tools, for example in their use as diagnostic aids for determining and distinguishing different types of hypertension, but also of atherosclerosis, of diabetes and late complications of diabetes, proliferative disorders etc.
The compounds of the formula I are moreover suitable for preventive therapy to prevent the development and for the treatment of high blood pressure, for example of essential hypertension, because they reduce or completely inhibit the re-absorption of NaCl in the tubular system of the kidneys. Accordingly, they are also outstandingly suitable as combination and formulation partners for drugs used for treating high blood pressure. Examples of possible combinations are diuretics having a thiazide-like action, loop diuretics, aldosterone and pseudo-aldosterone antagonists, such as hydrochlorothiazide, indapamide, polythiazide, furosemide, piretanide, torasemide, bumetanide, amiloride, triamterene. The NHE inhibitors of the present invention can further be used in combination with ACE inhibitors such as, for example, ramipril, enalapril or captopril. Further beneficial combination partners are also β-blockers.
The described NHE inhibitors can likewise be used in the prevention and for the treatment of thrombotic disorders because, as NHE inhibitors, they are able to inhibit both platelet aggregation itself and, in addition, able to inhibit or prevent the excessive release of coagulation mediators, in particular of von Willebrand factor. The NHE inhibitors of the present invention can therefore be combined with further anticoagulant active ingredients such as, for example, acetylsalicylic acid, thrombin antagonists, factor Xa antagonists, drugs with fibrinolytic activity, factor VIIa antagonists etc. Combined use of the present NHE inhibitors with NCBE inhibitors is particularly beneficial.
It has additionally been found that NHE inhibitors show a beneficial effect on serum lipoproteins. It is generally acknowledged that blood lipid levels which are too high, so-called hyper-lipoproteinemias, represent a considerable risk factor for the development of arteriosclerotic vascular lesions, especially coronary heart disease. The reduction of elevated serum lipoproteins therefore has exceptional importance for the prophylaxis and regression of atherosclerotic lesions. The compounds used according to the invention can therefore be used for the prophylaxis and regression of atherosclerotic lesions by eliminating a causal risk factor. The NHE inhibitors of the invention can also be combined in a beneficial manner with other anti-arteriosclerotic active ingredients such as a substance from the class of fibrates, an upregulator of LD2 receptor activity such as MD-700 and LY295427 or a cholesterol or bile acid absorption inhibitor or an anti-hyper-cholesterolemic agent from the class of statins, such as, for example, pravastatin, lovastatin, simvastatin.
With this protection of the vessels against the syndrome of endothelial dysfunction, compounds of the formula I are valuable drugs for the prevention and treatment of coronary vasospasms, peripheral vascular diseases such as intermittent claudication, of atherogenesis and of atherosclerosis, of left-ventricular hypertrophy and of dilated cardiomyopathy, and thrombotic disorders.
It has been possible to show that compounds of the formula I represent excellent inhibitors of the sodium-hydrogen exchanger (NHE), especially of the sodium-hydrogen exchanger of subtype 3 (NHE-3).
NHE-3 inhibitors disclosed to date are derived for example from compounds of the acylguanidine type (EP825178), norbornylamine type (WO0144164), 2-guanidino-quinazoline type (WO0179186) or benzamidine type (WO0121582, WO0172742). Squalamine, which is likewise described as an NHE-3 inhibitor (M. Donowitz et al. Am. J. Physiol. 276 (Cell Physiol. 45): C136-C144), does not according to current knowledge act directly like the compounds of formula I, but acts via an indirect mechanism and thus reaches its maximum strength of effect after only one hour.
Tetrahydroisoquinolines as inhibitors of the sodium-hydrogen exchanger of subtype 3 (NHE-3) are described for example in the patent applications WO03048129, WO2004085404 and the German applications 102004046492.8 and 102005001411.9. The related compound class of tetrahydroisoquinolinium salts is described as NHE-3 inhibitors in the patent application WO03055880.
It has now surprisingly been found that the compounds of the formula I described herein likewise represent potent inhibitors of NHE-3 and moreover have advantageous pharmacological and pharmacokinetic properties.
NHE-3 is found in the body of various species preferentially in the bile, the intestine and the kidney (Larry Fliegel et al, Biochem. Cell. Biol. 76: 735-741, 1998), but has also been detectable in the brain (E. Ma et al. Neuroscience 79: 591-603).
Because of their NHE-inhibitory properties, the compounds of the formula I are suitable for the prevention and treatment of diseases which are caused by activation of or by an activated NHE, and of diseases which are caused secondarily by the NHE-related damage.
The compounds of the formula I can also be employed for the treatment and prevention of diseases where NHE is only partially inhibited, for example by use of a lower dosage.
The use of the compounds of the invention relates to the prevention and treatment of acute and chronic diseases in veterinary and human medicine.
As a consequence of their pharmacological effects, the compounds of the formula I are particularly suitable for leading to an improvement in respiratory drive. They can therefore be used for the treatment of impaired respiratory conditions like those which may occur for example in the following clinical conditions and diseases: impaired central respiratory drive (e.g. central sleep apneas, sudden infant death, postoperative hypoxia), muscle-related respiratory impairments, respiratory impairments following long-term ventilation, respiratory impairments associated with adaptation to high altitude, obstructive and mixed form of sleep apneas, acute and chronic pulmonary diseases with hypoxia and hypercapnia. In addition, the compounds increase the tone of the muscles of the upper airways, so that snoring is suppressed. Said compounds are therefore advantageously used for the manufacture of a medicament for the prevention and treatment of sleep apneas and muscle-related respiratory impairments and for the manufacture of a medicament for the prevention and treatment of snoring.